The overall goal of our program is to develop more effective therapies for patients with thoracic cancers. This work falls under two main categories: 1. Exploiting mesothelin for cancer therapy. 2. Immunotherapy and other approaches to treat lung cancer, mesothelioma and thymic cancers. 1. Exploiting mesothelin for cancer therapy with a focus on mesothelioma and lung cancer. Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin, which is expressed on normal mesothelial cells lining the pleura, pericardium and peritoneum but is highly expressed in several human tumors especially mesothelioma, ovarian, lung and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. These include anti mesothelin immunotoxins (LMB-100) and an anti-mesothelin drug conjugate (BAY 94-9343). and a mesothelin vaccine (CRS-207). LMB-100 is an immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin, Pseudomonas exotoxin A, which has been de-immunized to decrease its antigenicity. We have recently completed the phase I trial of LMB-100 and established its safety and maximum tolerated dose. Currently we are doing a phase II study in patients with mesothelioma. We are also recently completed a phase I clinical trial to determine the safety and MTD of the anti-mesothelin antibody drug conjugate BAY 94-9343, which consists of a humanized anti-mesothelin monoclonal antibody linked to the maytansinoid DM4. We are now doing a phase I study of BAY 94-9343 in combination with chemotherapy. In the laboratory we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established and characterized several early passage tumor cells obtained from ascites and pleural fluid of patients with mesothelioma. We have fully characterized these cells for morphological and molecular characteristics. These models are essential to evaluate novel therapeutic agents for mesothelioma. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environmnet and changes following treatment with anti-mesothelin targeted agents. 2. Immunotherapy to treat lung cancer and thymic cancers. Thymic Cancers: Thymoma is a rare tumor characterized by infiltration of lymphocytes making them uniquely suitable for immune-checkpoint inhibition.Thymoma patients are currently being treated on a phase I clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C. We have seen remarkable anti-tumor activity in these patients that has been accompanied by side-effect profile unique to thymoma patients. In addition, we are conducting a Phase II study of sunitinib in thymic carcinomas. Lung Cancer: We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is, independently, associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open. Our laboratory is also studying the role of immune checkpoints in malignant mesothelioma so that drugs targeting this pathway can be exploited for treating mesothelioma.